The present invention relates to a pharmaceutical composition having neurotrophic activity, for treating peripheral and/or CNS-disorders in mammals.
GDF-5 is a bone morpho genetic protein like molecule which, similar to other members of the transforming growth factor beta (TGF-xcex2) superfamily, has been implicated in neurotrophic functions. For example, TGF-xcex21, -xcex22, and -xcex23, as well as activin A, bone morphogenetic proteins (BMP) -2, -4, -6, -7, -12, glial cell line-derived neurotrophic-like factors (GDNF-like), and GDF-5 have all been shown to promote in vitro the survival of midbrain dopaminergic neurons by various mechanisms. GDNF also acts on a wide spectrum of peripheral neurons.
The discovery of GDNF as a neurotrophic factor for midbrain dopaminergic neurons was a hallmark in the search for novel molecules that may have relevance in the treatment of neurodegenerative diseases, as e.g. Parkinson""s disease. The significance of GDNF is further underscored by its efficacy in several animal models of PD including non-human primates, ubiquitous expression in neurons of the CNS, and its widening spectrum of responsive neuron populations. GDNF signals via the tyrosine kinase receptor c-ret in co-operativity with a GPI-linked xcex1 receptor, the GDNFRxcex1. GDNF is a member of the TGF-xcex2 superfamily, its closest relatives being neurturin. Targeted mutations of the GDNF or c-Ret genes have indicated that GDNF is essentially required for the development of the kidney, major portions of the enteric nervous system and the sympathetic superior cervical ganglion. However, GDNF does not support the survival of most peripheral neurons in low-density dissociated cultures and defined media. Follow-up experiments in which GDNF has been shown to promote the survival of enriched peripheral autonomic and sensory neurons were all performed using serum throughout the whole culture period. Furthermore, the dopaminotrophic effect of GDNF was established in an extremely complex culture system where its most prominent effect did not become apparent until day 7 in culture.
TGF-xcex2s are widely distributed and contextually acting cytokines with prominent roles in development and cell cycle control. TGF-xcex2s have been implicated in the regulation of neuronal survival of e.g. motoneurons, sensory and midbrain dopaminergic neurons. It should be noted, however, that TGF-xcex2 shows no or marginal effects on highly enriched, serum-free neuron cultures, as e.g. sensory neurons.
Thus, the technical problem underlying the present invention is to provide a new system having improved neurotrophic activity, for the treatment of peripheral and/or CNS-disorders in mammals.
The solution to the above technical problem is achieved by the embodiments characterized in the claims.
In particular, the present invention relates to a pharmaceutical composition having a neurotrophic activity, comprising a biologically active amount of at least two cytokines or functionally active derivatives or parts thereof and optionally a pharmaceutically acceptable carrier and/or diluent, wherein at least one of said cytokines is BMP, GDF, TGF-xcex2 or GDNF. The term xe2x80x9cBMPxe2x80x9d includes BMP-2, BMP4, BMP-6, BMP-7, BMP-11 and BMP-12. The term xe2x80x9cTGF-xcex2xe2x80x9d includes TGF-xcex21, TGF-xcex22 and TGF-xcex23. The term xe2x80x9cGDNFxe2x80x9d includes GDNF, neurturin and persephin. The terms xe2x80x9cfunctionally active derivativexe2x80x9d and xe2x80x9cfunctionally active partxe2x80x9d refer to a proteinous compound exhibiting at least part of the biological function of the respective cytokine. The cytokines used in the pharmaceutical composition according to the present invention may be selected from the group consisting of GDF such as GDF-5, GDF-6, GDF-7, GDF-8 and GDF-9, GDNF, TGF such as TGF-xcex2 or TGF-xcex2, e.g. TGF-xcex21, TGF-xcex22 or TGF-xcex23, activin A, BMP such as BMP-2, BMP4, BMP6, BMP-7, BMP-11, BMP-12, BDNF, NGF, neurotrophines such as NT-3 or NT4, EGF, CNTF and FGF such as FGF-2.
Preferred embodiments of the present invention the pharmaceutical composition comprise the following combinations: GDF-5 and NGF or NT-3 or GDNF, TGF-xcex2 and GDNF or FGF-2 or CNTF or NT-3 or NGF, NGF and BMP-4 or BMP-12, NT-3 and BMP-2 or BMP-7 or BMP-12.
As a surprising fact, if at least one of BMP, GDF, TGF-xcex2 and GDNF is present in the above defined pharmaceutical composition, a synergistic effect can be observed resulting in an increased neurotrophic activity, as compared to e. g. known compositions without GDF and/or GNDF.
The pharmaceutical composition according to the present invention may be used for the treatment of peripheral and/or CNS-disorders in mammals, preferably in man, such as Parkinson""s disease, Alzheimer""s disease, ALS or other dementia, other neurodegenerative disorders of the central nervous system and peripheral neuropathies including diabetes, cisplatinium or other genetic or acquired peripheral nerve diseases.